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Updated: Jul 30, 2025
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Detecting recurrent passenger mutations in melanoma by targeted UV damage sequencing
Kathiresan Selvam1, Smitha Sivapragasam1, Gregory M K Poon2
1School of Molecular Biosciences, Washington State University, Pullman, WA, 99164, USA.
Abstract:
Sequencing of melanomas has identified hundreds of recurrent mutations in both coding and non-coding DNA. These include a number of well-characterized oncogenic driver mutations, such as coding mutations in the BRAF and NRAS oncogenes, and non-coding mutations in the promoter of telomerase reverse transcriptase (TERT). However, the molecular etiology and significance of most of these mutations is unknown. Here, we use a new method known as CPD-capture-seq to map UV-induced cyclobutane pyrimidine dimers (CPDs) with high sequencing depth and single nucleotide resolution at sites of recurrent mutations in melanoma. Our data reveal that many previously identified drivers and other recurrent mutations in melanoma occur at CPD hotspots in UV-irradiated melanocytes, often associated with an overlapping binding site of an E26 transformation-specific (ETS) transcription factor. In contrast, recurrent mutations in the promoters of a number of known or suspected cancer genes are not associated with elevated CPD levels. Our data indicate that a subset of recurrent protein-coding mutations are also likely caused by ETS-induced CPD hotspots. This analysis indicates that ETS proteins profoundly shape the mutation landscape of melanoma and reveals a method for distinguishing potential driver mutations from passenger mutations whose recurrence is due to elevated UV damage.
Insights
UV radiation causes DNA damage, leading to mutations in melanoma. This study reveals that many melanoma mutations occur at UV-induced damage hotspots, often influenced by ETS transcription factors, helping distinguish driver from passenger mutations.
Area of Science:
- Genomics
- Cancer Biology
- Molecular Oncology
Background:
- Melanoma sequencing reveals numerous recurrent mutations in coding and non-coding DNA, including known oncogenic drivers like BRAF, NRAS, and TERT promoter mutations.
- The molecular origins and functional significance of most identified melanoma mutations remain largely unknown.
- Understanding mutation drivers is crucial for targeted therapies and deciphering melanoma pathogenesis.
Purpose of the Study:
- To investigate the role of UV-induced DNA damage in shaping the melanoma mutation landscape.
- To identify specific mutation hotspots and their association with UV damage and transcription factor binding.
- To develop a method for distinguishing driver mutations from passenger mutations in melanoma.
Main Methods:
- Utilized CPD-capture-seq, a novel technique, to map UV-induced cyclobutane pyrimidine dimers (CPDs) at single nucleotide resolution.
- Analyzed recurrent mutation sites in melanoma, correlating them with CPD levels in UV-irradiated melanocytes.
- Examined the overlap between mutation hotspots, CPDs, and transcription factor binding sites, particularly E26 transformation-specific (ETS) factors.
Main Results:
- Many recurrent melanoma mutations, including previously identified drivers, were found at CPD hotspots in UV-exposed melanocytes.
- These hotspots frequently overlapped with binding sites for ETS transcription factors.
- Recurrent mutations in certain cancer gene promoters were not associated with elevated CPD levels.
- A subset of recurrent protein-coding mutations are likely driven by ETS-induced CPD hotspots.
Conclusions:
- UV-induced DNA damage and ETS transcription factors significantly influence the mutation landscape of melanoma.
- CPD-capture-seq provides a powerful method to differentiate driver mutations from passenger mutations caused by UV damage.
- This research offers new insights into melanoma etiology and potential therapeutic targets.
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